Obesity has reached epidemic proportions and poses serious public health challenges, in particular type 2[unreadable] diabetes, cardiovascular disease, sleep apnea, osteoarthritis and cancer. Adipocyte hormones may provide[unreadable] key insights into the pathogenesis of obesity-related diseases. Leptin and adiponectin stimulate fatty acid[unreadable] oxidation, decrease lipid levels and increase insulin sensitivity. In contrast, resistin decreases insulin[unreadable] sensitivity, and increases glucose and lipids. Leptin acts in the CMS to suppress appetite and increase[unreadable] energy expenditure, but also has direct effects on peripheral tissues. Adiponectin and resistin have direct[unreadable] actions on liver and muscle, but recent observations suggest that these adipokines also have central effects.[unreadable] We hypothesize that the divergent effects of these adipocytes on metabolism are mediated, at least in part,[unreadable] through distinct neuronal targets and signaling pathways in the hypothalamus. Specific Aim 1 will compare[unreadable] the effects of CMS administration of leptin, adiponectin and resistin on energy and glucose metabolism. We[unreadable] will examine the regulation of peripheral glucose fluxes using insulin clamp and radioactive tracer kinetics.[unreadable] Based on our preliminary studies showing an attenuation of the CMS effects of leptin and adiponectin in[unreadable] agouti mice, we will determine whether the opposite effects of leptin/adiponectin versus resistin on glucose[unreadable] levels is mediated through melanocortin (MC)4 receptor signaling. Specific Aim 2 will determine the sites of[unreadable] action of these adipocyte hormones in the hypothalamus, using Fos immunohistochemistry and in situ[unreadable] hybridization. Finally, Specific Aim 3 will determine whether the opposing metabolic effects of leptin,[unreadable] adiponectin and resistin occur through AMP-kinase and SOCS-3 in the hypothalamus. We will test the[unreadable] hypothesis that central administration of resistin antagonizes the central effects of leptin and adiponectin on[unreadable] metabolism, through reciprocal regulation of AMPK, SOC-3, or both signaling pathways. Understanding the[unreadable] hypothalamic and signaling pathways that mediate the effects of leptin, adiponctin and resistin will provide[unreadable] novel insights into the pathophysiology of obesity and diabetes that will facilitate novel diagnostic and[unreadable] treatment strategies.